The effect of varying water volumes on in vivo dissolution and gastric emptying of highly soluble caffeine and lesser soluble theobromine containing capsules.

The influence of co-administered water volume on the intragastric dissolution and the systemic exposure of drugs taken under fed conditions remains clinically relevant, particularly for drug substances with limited aqueous solubility. This secondary pharmacokinetic analysis, based on a previously published MRI study (n = 12) evaluated the effect of 50, 100, and 150 mL water on the salivary pharmacokinetics of 13C₃-caffeine (25 mg; high solubility, high permeability) and theobromine (50 mg; lower solubility, high permeability) administered in a hard gelatin capsule 30 min after a standardized meal. Saliva samples were collected over 119 min and quantified by LC-MS/MS. Both compounds appeared rapidly in saliva irrespective of the initial water volume, indicating that even 50 mL effectively triggered postprandial liquid emptying via the Magenstrasse. Wilcoxon Signed-Rank test of dose-normalized AUC0 - 119 min demonstrated no significant differences between both substances. Phase-specific analysis (0-59 min vs. 59-119 min) revealed a strong phase effect (p < 0.001) and a significant phase × substance interaction (p < 0.001), but no effect of initial fluid volume, reflecting a pronounced late exposure increase for theobromine after administration of an additional 240 mL water at 60 min. These findings indicate that small fluid volumes are sufficient to initiate rapid gastric transit of dissolved fractions under fed conditions. However, for less soluble compounds, undissolved fractions may persist intragastrically and contribute to delayed, biphasic absorption following subsequent fluid intake. Standardization of post-dose drinking behavior should therefore be considered in food-effect and bioavailability studies.